Intracerebral hemorrhage (ICH) is the most devastating subtype of stroke with high mortality rates, and
profound morbidity and disability. The mechanisms leading to brain damage caused by ICH are multifaceted
and poorly understood. There is no FDA approved treatment for ICH.
Recent studies and our preliminary work indicate that astrocytes, cells known to have a uniquely dense network
of mitochondria (Mt), secrete intact Mt, which upon entering adjacent neurons or microglia could help them resist
injury and promote restorative function when exposed to the damage effects of intracerebral blood products.
While the biology of Mt transfer is seen as homeostatic, the mechanisms behind their beneficial effect is unclear.
One of the unique functions of Mt is to produce, from its own genome, a small potent bioactive secretory peptide,
humanin (HN; encoded in the Mt DNA 16S ribosomal RNA region), which acts through a specific surface receptor
present in the brain, including on neurons and microglia. HN is implicated in Mt-associated longevity and has
cytoprotective activities. However, the mechanism behind these beneficial effects of HN in cerebrovascular
diseases and its clinical relevance remains unclear.
Our extensive preliminary results demonstrate: (1) a robust Mt transfer from astrocytes to neurons or to microglia
and that the transfer confers cytoptotection in neurons and a “healing” phenotype in microglia under ICH-like
conditions. (2) ICH-mediated injury in mice results in a profound loss of HN in the ICH-affected hemisphere and
treatment with recombinant HN (rHN) significantly reduced neurological deficits produced by ICH. (3) HN or
astrocytic Mt-transfer into neurons leads to (a) STAT3/MnSOD upregulation and reduction of oxidative damage
to neurons, and (b) PPAR¿ upregulation in microglia and a “healing” phenotype, including increased phagocytic
Therefore, we hypothesize that Mt-derived HN, released or transferred within the intact Mt secreted from
astrocytes (or injected as recombinant HN, rHN) can reduce ICH-mediated damage (1) by increasing neuronal
resistance to oxidative damage (through upregulating Mt anti-oxidative Mn-SOD) and by supporting neural
plasticity; and (2) by securing “healing” (phagocytic/anti-oxidative/anti-inflammatory/trophic) phenotype of
microglia, through transcription factor PPAR¿.
Our specific aims are: (1) To establish (in vitro) the cellular mechanisms by which astrocytic HN and Mt transfer
(A) attenuates injury to neurons and (B) promotes the “healing” phenotype to microglia under conditions
simulating ICH. (2) To determine (in vivo) the translational value and mechanism by which Mt/HN mediates
protection from damage imposed by ICH. (3) To establish age/sex-related differences in Mt transfer, and HN
expression by using aged male and female mice, and the therapeutic effect of HN in ICH.